This invention describes the synthesis of the poly (ADP-ribose) polymerase (PARP) inhibitor, 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, comprising an optimized copper-catalyzed carbon-nitrogen coupling process utilizing a protecting group strategy. A crucial step in the synthesis of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide includes coupling of a key piperidine intermediate with N-2 of a key indazole intermediate. Protecting a primary amide of the parent indazole used in the cross-coupling reaction results in a more efficient process with improved reactivity and regioselective N-2 arylation.
Buchwald et al. (U.S. Pat. No. 6,235,936) describes methods for the metal-catalyzed arylation of hydrazines, hydrazones, hydroxylamines and/or oximes through the formation of a carbon-heteroatom bond between an aromatic compound comprising an activated carbon bearing a leaving group and a heteroatom of a hydrazine, hydrazone, hydroxylamine or oxime.
PCT International Appl. No. PCT/US02/12785 (published WO 2002085838) describes copper-catalyzed methods for forming carbon-carbon and carbon-heteroatom bonds.
U.S. Pat. No. 8,071,623 describes PARP inhibitors, including 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and a synthesis of this compound.
Wallace et al. (2011, Organic Process Research and Development 15:831-840) describes large-scale synthesis (up to 5 kg) routes of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide relying on either classical resolution or chiral separation.